This Mentored Research Scientist Development Award (K01) is to develop the research program of Dr. Joong-Youn Shim in the Julius L. Chambers Biomedical/Biotechnology Research Institute (JLC-BBRI) at North Carolina Central University (NCCU). To achieve the scientific goals, protein modeling will be utilized for the study the ligand-CB1 receptor-Galphai complex under the supervision of computational and pharmacology experts. The current proposal will allow to obtain solid and broad knowledge of protein modeling and will lead to be equipped with capability to address many challenging issues important in biomedical research area in the future. This research will be supervised by Dr. Thomas Darden (Principal Investigator, Laboratory of Structural Biology, National Institute of Environmental Health Sciences, RTF, NC) as the scientific mentor and Dr. Allyn C. Hewlett (Director, Neurosci./Drug Abuse Res. Program, JLC-BBRI, Durham, NC) as the scientific comentor, and Drs. Brian Thomas (Director, Center for Chemistry Services, Research Triangle Institute, RTP, NC) and Emad Tajkhorshid (Assistant Director of Research, Theoretical &Computational Biophysics Group, University of Illinois at Urbana-Champaign, Beckman Institute, IL) as the scientific advisory members. The major goal of the proposed research is to demonstrate that the ligand can trigger to induce or stabilize receptor serial micro-conformational changes requisite to G-protein activation by using a protein MD simulations approach. The SPECIFIC AIMS are: 1) Construction of a molecular model, including the transmembrane (TM) helices, the extracellular/ intracellular loops, and the shortened N- and C-terminals of the brain CB1 receptor in complex with GalphaM;2) Protein MD simulations of the CB1 receptor-Galphai 1 complex;3) Conversion of the inactive CB1 receptor to its active form by protein MD simulations of the ligand-CB1 receptor-Galphah complex;and 4) Analysis of the protein MD simulation results.